Competing Charge Transfer and Screening Effects in Two-Dimensional Ferroelectric Capacitors.

Two-dimensional (2D) ferroelectrics promise ultrathin flexible nanoelectronics, typically utilizing a metal-ferroelectric-metal sandwich structure. Electrodes can either contribute free carriers to screen the depolarization field, enhancing nanoscale ferroelectricity, or induce charge doping, disrupting the long-range crystalline order. We explore electrodes' dual roles in 2D ferroelectric capacitors, supported by first-principles calculations covering a range of electrode work functions. Our results reveal volcano-type relationships between ferroelectric-electrode binding affinity and work function, which are further unified by a quadratic scaling between the binding energy and the transferred interfacial charge. At the monolayer limit, charge transfer dictates the ferroelectric stability and switching properties. This general characteristic is confirmed in various 2D ferroelectrics including α-In2Se3, CuInP2S6, and SnTe. As the ferroelectric layer's thickness increases, the capacitor stability evolves from a charge-transfer-dominated state to a screening-dominated state. The delicate interplay between these two effects has important implications for 2D ferroelectric capacitor applications.

Sirt1 alleviates osteoarthritis via promoting FoxO1 nucleo-cytoplasm shuttling to facilitate autophagy.

This study aims to investigate the role and underlying mechanisms of Sirt1 in the pathophysiological process of OA. Safranine O and HE staining were utilized to identify pathological changes in the cartilage tissue. Immunohistochemistry was employed to evaluate the expression levels of proteins. IL-1ß treatment and TamCartSirt1flox/flox mice were utilized to induce OA model both in vitro and in vivo. Key autophagy-related transcription factors, autophagy-related genes, and chondrocyte extracellular matrix (ECM) breakdown enzyme markers were examined using multi assays. Immunofluorescence staining revealed subcellular localization and gene expression patterns. ChIP assay and Co-immunoprecipitation assay were conducted to investigate the interactions between FoxO1 and the promoter regions of Atg7 and Sirt1. Our results demonstrate that Sirt1 deficiency exhibited inhibitory effects on ECM synthesis and autophagy, as well as exacerbated angiogenesis. Moreover, Atg7, Foxo1, and Sirt1 could form a protein complex. Sirt1 was observed to facilitate nuclear translocation of FoxO1, enhancing its transcriptional activity. Furthermore, FoxO1 was found to bind to the promoter regions of Atg7 and Sirt1, potentially regulating their expression. This study provides valuable insights into the involvement of Sirt1-Atg7-FoxO1 loop in OA, opening new avenues for targeted therapeutic interventions aiming to mitigate cartilage degradation and restore joint function.

Perturbation diversity certificates robust generalization.

Whilst adversarial training has been proven to be one most effective defending method against adversarial attacks for deep neural networks, it suffers from over-fitting on training adversarial data and thus may not guarantee the robust generalization. This may result from the fact that the conventional adversarial training methods generate adversarial perturbations usually in a supervised way so that the resulting adversarial examples are highly biased towards the decision boundary, leading to an inhomogeneous data distribution. To mitigate this limitation, we propose to generate adversarial examples from a perturbation diversity perspective. Specifically, the generated perturbed samples are not only adversarial but also diverse so as to certify robust generalization and significant robustness improvement through a homogeneous data distribution. We provide theoretical and empirical analysis, establishing a foundation to support the proposed method. As a major contribution, we prove that promoting perturbations diversity can lead to a better robust generalization bound. To verify our methods' effectiveness, we conduct extensive experiments over different datasets (e.g., CIFAR-10, CIFAR-100, SVHN) with different adversarial attacks (e.g., PGD, CW). Experimental results show that our method outperforms other state-of-the-art (e.g., PGD and Feature Scattering) in robust generalization performance.

Inhibition of MEG3 ameliorates cardiomyocyte apoptosis and autophagy by regulating the expression of miRNA-129-5p in a mouse model of heart failure.

The long non-coding RNA, maternally expressed gene 3 (MEG3), are involved in myocardial fibrosis and compensatory hypertrophy, but its role on cardiomyocyte apoptosis and autophagy in heart failure (HF) remains unclear. The aim of this study was to investigate the effect of MEG3 on cardiomyocyte apoptosis and autophagy and the underlying mechanism. A mouse model of HF was established by subcutaneous injection of isoproterenol (ISO) for 14 days, and an in vitro oxidative stress injury model was replicated with H2O2 for 6 h. SiRNA-MEG3 was administered in mice and in vitro cardiomyocytes to knock down MEG3 expression. Our results showed that cardiac silencing of MEG3 can significantly ameliorate ISO-induced cardiac dysfunction, hypertrophy, oxidative stress, apoptosis, excessive autophagy and fibrosis induced by ISO. In addition, inhibition of MEG3 attenuated H2O2-induced cardiomyocyte oxidative stress, apoptosis and autophagy in vitro. Downregulation of MEG3 significantly inhibited excessive cardiomyocyte apoptosis and autophagy induced by ISO and H2O2 through miRNA-129-5p/ATG14/Akt signaling pathways, and reduced H2O2-induced cardiomyocyte apoptosis by inhibiting autophagy. In conclusion, inhibition of MEG3 ameliorates the maladaptive cardiac remodeling induced by ISO, probably by targeting the miRNA-129-5p/ATG14/Akt signaling pathway and may provide a tool for pharmaceutical intervention.

Automated design of freeform imaging systems for automotive heads-up display applications.

The freeform imaging system is playing a significant role in developing an optical system for the automotive heads-up display (HUD), which is a typical application of augmented reality (AR) technology. There exists a strong necessity to develop automated design algorithms for automotive HUDs due to its high complexity of multi-configuration caused by movable eyeballs as well as various drivers' heights, correcting additional aberrations introduced by the windshield, variable structure constraints originated from automobile types, which, however, is lacking in current research community. In this paper, we propose an automated design method for the automotive AR-HUD optical systems with two freeform surfaces as well as an arbitrary type of windshield. With optical specifications of sagittal and tangential focal lengths, and required structure constraints, our given design method can generate initial structures with different optical structures with high image quality automatically for adjusting the mechanical constructions of different types of cars. And then the final system can be realized by our proposed iterative optimization algorithms with superior performances due to the extraordinary starting point. We first present the design of a common two-mirror HUD system with longitudinal and lateral structures with high optical performances. Moreover, several typical double mirror off-axis layouts for HUDs were analyzed from the aspects of imaging performances and volumes. The most suitable layout scheme for a future two-mirror HUD is selected. The optical performance of all the proposed AR-HUD designs for an eye-box of 130 mm × 50 mm and a field of view of 13° × 5° is superior, demonstrating the feasibility and superiority of the proposed design framework. The flexibility of the proposed work for generating different optical configurations can largely reduce the efforts for the HUD design of different automotive types.

A Genetic Variant of FAM46A is Associated With the Development of Adolescent Idiopathic Scoliosis in the Chinese Population.

STUDY DESIGN: A genetic case-control study. OBJECTIVE: To replicate recently reported genetic loci associated with adolescent idiopathic scoliosis (AIS) in the Chinese Han population, and to determine the relationship between gene expression and the clinical features of the patients. SUMMARY OF BACKGROUND DATA: A recent study conducted in the Japanese population identified several novel susceptible loci, which might provide new insights into the etiology of AIS. However, the association of these genes with AIS in other populations remains unclear. MATERIALS AND METHODS: A total of 1210 AIS and 2500 healthy controls were recruited for the genotyping of 12 susceptibility loci. Paraspinal muscles used for gene expression analysis were obtained from 36 AIS and 36 patients with congenital scoliosis. The difference regarding genotype and allele frequency between patients and controls was analyzed by χ 2 analysis. The t test was performed to compare the target gene expression level between controls and AIS patients. Correlation analysis was performed between gene expression and phenotypic data, including Cobb angle, bone mineral density, lean mass, height, and body mass index. RESULTS: Four SNPs, including rs141903557, rs2467146, rs658839, and rs482012, were successfully validated. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of single nucleotide polymorphism rs482012 showed significantly higher frequency in patients. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of rs482012 could notably increase the risk of AIS patients, with an odds ratio of 1.49, 1.16, 1.11, and 1.25, respectively. Moreover, tissue expression of FAM46A was significantly lower in AIS patients as compared with controls. Moreover, FAM46A expression was remarkably correlated with bone mineral density of patients. CONCLUSION: Four SNPs were successfully validated as novel susceptibility loci associated with AIS in the Chinese population. Moreover, FAM46A expression was associated with the phenotype of AIS patients.

Towards the high-quality development of City Region Food Systems: Emerging approaches in China.

The outbreak of COVID-19 has underscored the vulnerability of our current food systems. In China, following a series of strategies in guaranteeing food security in the past decades, the pandemic has further highlighted the necessity to strengthen urban-rural linkages and facilitate the sustainable development of local agri-food systems. The study for the first time introduced the City Region Food Systems (CRFS) approach to Chinese cities and attempted to holistically structure, analyze and promote the sustainability of local food systems in China. Taking Chengdu as an example, the study first took stock of existing concepts and policies in China and the city, and defined the high-quality development goals of CRFS for Chengdu. An indicator framework was then developed to serve as a CRFS assessment tool for identifying existing challenges and potentials of local food systems. Further, a rapid CRFS scan using the framework was conducted in Chengdu Metropolitan Area, providing concrete evidence for potential policy interventions and practice improvement in the area. The study has explored new paradigm of analysis for food related issues in China and provided supporting tools for evidence-based food planning in cities, which collectively contribute to the food system transformation in a post-pandemic scenario.

Cartilage-specific deficiency of clock gene Bmal1 accelerated articular cartilage degeneration in osteoarthritis by up-regulation of mTORC1 signaling.

Although a growing body of studies recently demonstrated that circadian clock gene Bmal1 plays an important role in cartilage development and homeostasis, evidence regarding the contribution of Bmal1 in articular cartilage of OA progression is still unclear. In the present study, we investigated the direct role of Bmal1 in articular cartilage homeostasis during OA progression using tamoxifen-induced cartilage-specific knockout mice. We found that the expression of BMAL1 was decreased in OA-damaged and aging cartilage tissues. Cartilage-specific deletion of Bmal1 promoted cartilage degradation and chondrocyte apoptosis, and inhibited chondrocyte anabolism in OA mice, leading to acceleration of articular cartilage degeneration and osteophyte formation during OA progression. Mechanistic study indicated that loss of Bmal1 resulted in hyperactivation of mammalian target of rapamycin complex 1(mTORC1) signaling in OA cartilage, and pharmacological inhibition of mTORC1 signaling pathway by rapamycin alleviated partially Bmal1 ablation-induced cartilage degradation and chondrocyte apoptosis in ex vivo OA model. Therefore, our results provide the evidence of a vital role for Bmal1 in cartilage degradation in post-traumatic OA by partially regulating the mTORC1 signaling.

Blocking circadian clock factor Rev-erbα inhibits growth plate chondrogenesis via up-regulating MAPK-ERK1/2 pathway.

Emerging evidence indicated circadian clock gene Rev-erbα was involved in cartilage metabolism, however the contribution of Rev-erbα to growth plate chondrogenesis remains unknown. Here, we found that Rev-erbα exhibited the spatiotemporal expression model in growth plate. Moreover, Rev-erbα antagonist SR8278 inhibited longitudinal elongation of metatarsal bone ex vivo. And morphological analysis exhibited SR8278 led to the reduced height of growth plate and hypertrophic zone. Furthermore, blocking Rev-erbα suppressed the proliferation and hypertrophic differentiation of chondrocytes in growth plate. Similarly, knock-down Rev-erbα inhibited the proliferation and differentiation of primary chondrocytes in vitro. The mechanistic study indicated that knock-down Rev-erbα up-regulated MAPK-ERK1/2 pathway in chondrocytes. However, restraint of MAPK-ERK1/2 pathway alleviated partially SR8278-inhibited longitudinal elongation of metatarsal bone and growth plate development. Therefore, our results provide evidence of the vital role of Rev-erbα on growth plate chondrogenesis.

Synthesis and Biological Evaluation of PEGylated MWO4 Nanoparticles as Sonodynamic AID Inhibitors in Treating Diffuse Large B-Cell Lymphoma.

Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its ability to overcome critical limitations, including low tissue-penetration depth and phototoxicity in photodynamic therapy (PDT). Biogenic metal oxide nanoparticles (NPs) have been used as anti-cancer drugs due to their biocompatibility properties with most biological systems. Here, sonosensitizer MWO4-PEG NPs (M = Fe Mn Co Ni) were synthesized as inhibitors to activation-induced cytidine deaminase (AID), thus neutralizing the extensive carcinogenesis of AID in diffuse large B-cell lymphoma (DLBCL). The physiological properties of these nanomaterials were examined using transmission electron microscopy (TEM). The inhibition of NPs to AID was primarily identified by the affinity interaction prediction between reactive oxygen species (ROS) and AID through molecular dynamics and molecular docking technology. The cell apoptosis and ROS generation in US-triggered NPs treated DLBCL cells (with high levels of AID) were also detected to indicate the sonosensitivity and toxicity of MWO4-PEG NPs to DLBCL cells. The anti-lymphoma studies using DLBCL and AID-deficient DLBCL cell lines indicated a concentration-dependent profile. The synthesized MWO4-PEG NPs in this study manifested good sonodynamic inhibitory effects to AID and well treatment for AID-positive hematopoietic cancers.

Relook into the Risk Factors of Proximal Junctional Kyphosis in Early Onset Scoliosis Patients: Does the Location of Upper Instrumented Vertebra in Relation to the Sagittal Apex Matter?

OBJECTIVE: Growing rods surgery is the mainstay of treatment for early-onset scoliosis (EOS) while proximal junctional kyphosis (PJK) is one of the most commonly reported postoperative complications. We sought to investigate the impact of the location of upper instrumented vertebra (UIV) in relation to the sagittal apex on proximal junctional kyphosis in EOS after traditional growing rods (GRs) treatment. METHODS: A total of 102 EOS patients who received traditional growing rods treatment with a follow-up of at least 2 years between 2009 and 2020 were retrospectively reviewed. Radiographic measurements were performed before and after the index surgery and at the latest follow-up. We investigated the coronal Cobb angle and spinopelvic parameters of the whole spine. The location of the UIV, apex, lower instrumented vertebra (LIV), inflection vertebra (IV), the number and distance of UIV-apex, LIV-apex and IV-apex were also recorded. Risk factors for PJK were analyzed by logistic regression analysis. RESULTS: PJK was observed in 21 patients (20.6%) during the follow-up period. The PJK group showed a younger age at the index surgery (5.9 vs. 7.1 years, P = 0.042), more lengthening procedure times (5.0 vs. 4.0, P = 0.032), larger preoperative coronal Cobb angle (82.0 vs. 75.6°, P = 0.038), higher correction rate (51.2% vs. 44.4%, P = 0.047) and larger postoperative proximal junctional angle (PJA) (13.9 vs. 5.5°, P < 0.001) than the non-PJK group. The ratio of the number and distance from UIV-apex to IV-apex also differed significantly between the two groups. The logistic regression revealed that age at the index surgery ≤ 7 years, the ratio of the number from UIV- apex to IV- apex ≤ 0.6 and the ratio of the distance from UIV- apex to IV- apex ≤ 0.6 were independent risk factors for postoperative PJK. CONCLUSION: Besides younger age, a closer location of UIV relative to the sagittal apex is identified to be an independent risk factor of postoperative PJK. Selection of UIV at a relatively farther location away from the sagittal apex might help prevent occurrence of PJK.

Galectin-3 Enhances Osteogenic Differentiation of Precursor Cells From Patients With Diffuse Idiopathic Skeletal Hyperostosis via Wnt/ß-Catenin Signaling.

Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory skeletal disease characterized by the progressive ectopic ossification and calcification of ligaments and enthuses. However, specific pathogenesis remains unknown. Bone marrow mesenchymal stem cells (BMSCs) are a major source of osteoblasts and play vital roles in bone metabolism and ectopic osteogenesis. However, it is unclear whether BMSCs are involved in ectopic calcification and ossification in DISH. The current study aimed to explore the osteogenic differentiation abilities of BMSCs from DISH patients (DISH-BMSCs). Our results showed that DISH-BMSCs exhibited stronger osteogenic differentiation abilities than normal control (NC)-BMSCs. Human cytokine array kit analysis showed significantly increased secretion of Galectin-3 in DISH-BMSCs. Furthermore, Galectin-3 downregulation inhibited the increased osteogenic differentiation ability of DISH-BMSCs, whereas exogenous Galectin-3 significantly enhanced the osteogenic differentiation ability of NC-BMSCs. Notably, the increased Galectin-3 in DISH-BMSCs enhanced the expression of ß-catenin as well as TCF-4, whereas attenuation of Wnt/ß-catenin signaling partially alleviated Galectin-3-induced osteogenic differentiation and activity in DISH-BMSCs. In addition, our results noted that Galectin-3 interacted with ß-catenin and enhanced its nuclear accumulation. Further in vivo studies showed that exogenous Galectin-3 enhanced ectopic bone formation in the Achilles tendon in trauma-induced rats by activating Wnt/ß-catenin signaling. The current study indicated that enhanced osteogenic differentiation of DISH-BMSCs was mainly attributed to the increased secretion of Galectin-3 by DISH-BMSCs, which enhanced ß-catenin expression and its nuclear accumulation. Our study helps illuminate the mechanisms of pathological osteogenesis and sheds light on the possible development of potential therapeutic strategies for DISH treatment. © 2022 American Society for Bone and Mineral Research (ASBMR).

Epigenetic regulation of chondrocyte hypertrophy and apoptosis through Sirt1/P53/P21 pathway in surgery-induced osteoarthritis.

Sirt1 involved in cellular aging and aging-related diseases, including osteoarthritis (OA). Our previous study showed Sirt1 played a role in the pathogenesis of OA, however, the underlying mechanisms are still poorly elicited. In this study, we investigated the role of Sirt1 in epigenetically regulating P53/P21 pathway in a Sirt1 loss model. Sirt1 deletion male mice (n = 10) with destabilization of the medial meniscus (DMM) were used to observe its role on OA development. Then, the relationships between SIRT1 and P53 were detected by Coimmunoprecipitation (CoIP), and the gain-off function of P53 gene was indicated by P53 activators and inhibitors in vitro. Finally, human cartilage samples from patients with OA were collected. Sirt1 deletion mice displayed a spontaneous OA development, manifesting severe chondrocytes hypertrophy markers MMP13 and ADAMTS5, highly expressed P53 and P21. Strikingly, surgery-induced meniscus injury promoted the OA pathogenesis and apoptosis in Sirt1 deficient mice. Ultimately, our CoIP data demonstrated that Sirt1 directly interacted with P53 in vitro. However inhibition of P53 alleviated OA progression. We also observed that chondrocyte apoptosis and P53 increased in osteoarthritis (OA) progression with a declining expression of Sirt1 in human cartilage. Loss of Sirt1 in cartilage led to accelerated OA pathogenesis via aberrant activation of p53/p21 mediated senescence associated secretory phenotype, hypertrophy and apoptosis.

Postnatal Conditional Deletion of Bmal1 in Osteoblasts Enhances Trabecular Bone Formation Via Increased BMP2 Signals.

A large number of studies in recent years indicated the involvement of peripheral circadian clock in varied pathologies. However, evidence regarding how peripheral clocks regulate bone metabolism is still very limited. The present study aimed to investigate the direct role of Bmal1 (the key activator of peripheral circadian clock system) in vivo during bone developmental and remodeling stages using inducible osteoblast-specific Bmal1 knockout mice. Unexpectedly, the removal of Bmal1 in osteoblasts caused multiple abnormalities of bone metabolism, including a progressive increase in trabecular bone mass in as early as 8 weeks, manifested by an 82.3% increase in bone mineral density and 2.8-fold increase in bone volume per tissue volume. As mice age, an increase in trabecular bone mass persists while cortical bone mass decreases by about 33.7%, concomitant with kyphoscoliosis and malformed intervertebral disk. The increased trabecular bone mass is attributed to increased osteoblast number and osteoblast activity coupled with decreased osteoclastogenesis. Remarkably, the ablation of Bmal1 in osteoblasts promoted the expression level of Bmp2 and phosphorylation of SMAD1, whereas the attenuation of BMP2/SMAD1 signaling partially alleviated the effects of Bmal1 deficiency on osteoblast differentiation and activity. The results revealed that Bmal1 was a transcriptional silencer of Bmp2 by targeting the Bmp2 promoter. The peripheral clock gene Bmal1 in osteoblasts was crucial to coordinate differential effects on trabecular and cortical bones through regulating BMP2/SMAD1 during bone development, thus providing novel insights into a key role of osteoblast Bmal1 in homeostasis and integrity of adult bones. © 2020 American Society for Bone and Mineral Research.

Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R.

Neuropeptide Y (NPY) is known to regulate bone homeostasis; however, its functional role as a risk factor during osteoarthritis (OA) remains elusive. In this study, we aim to investigate the direct effect of NPY on degradation of cartilage and progression of OA and explore the molecular events involved. NPY was overexpressed in human OA cartilage accompanied with increased expression of NPY1 receptor (NPY1R) and NPY2 receptor (NPY2R). Stressors such as cold exposure resulted in the peripheral release of NPY from sympathetic nerves, which in turn promoted upregulation of NPY and NPY2R in articular cartilage in vivo. Intra-articular administration of NPY significantly promoted chondrocyte hypertrophy and cartilage matrix degradation, with a higher OARSI score than that of control mice, whereas inhibition of NPY2R but not NPY1R with its specific antagonist remarkably ameliorated NPY-mediated effects. Moreover, NPY activated mTORC1 pathway in articular chondrocytes, whereas the administration of rapamycin (an mTORC1 inhibitor) in vitro abrogated NPY-mediated effects. Mechanistically, mTORC1 downstream kinase S6K1 interacted with and phosphorylated SMAD1/5/8 and promoted SMAD4 nuclear translocation, resulting in upregulation of Runx2 expression to promote chondrocyte hypertrophy and cartilage degradation. In conclusion, our findings provided the direct evidence and the crucial role of NPY in cartilage homeostasis. © 2020 American Society for Bone and Mineral Research.

PGRN exerts inflammatory effects via SIRT1-NF-κB in adipose insulin resistance.

Progranulin (PGRN), a multifunctional protein implicated in embryonic development and immune response, was recently introduced as a novel marker of chronic inflammation related with insulin resistance in obesity and type 2 diabetes mellitus. However, the potential mechanisms of PGRN on insulin signaling pathways are poorly understood. In this study, PGRN mediated the chemotaxis of RAW264.7, impaired insulin action and stimulated production of inflammatory factors in adipocytes, which was accompanied by increased c-Jun N-terminal kinase (JNK) activation and serine phosphorylation of insulin receptor substrate-1. PGRN knockdown partially led to an increase in insulin action as well as a decrease in the JNK activation and extracellular signal-regulated kinase phosphorylation in cells exposed to tumor-necrosis factor-α (TNF-α). Meanwhile, PGRN treatment resulted in an elevation of transcription factor nuclear factor κB (NF-κB) nuclear translocation and acetylation, and increased Il-1b, Il6, Tnf-a expression, whereas NF-κB inhibition reversed PGRN-induced insulin action impairment and inflammatory gene expression. Finally, we showed that sirtuin 1 (SIRT1) expression was downregulated by PGRN treatment, whereas SIRT1 overexpression improved PGRN-induced insulin resistance, NF-κB activation, and inflammatory gene expression. Our results suggest that PGRN regulates adipose tissue inflammation possibly by controlling the gain of proinflammatory transcription in a SIRT1-NF-κB dependent manner in response to inducers such as fatty acids and endoplasmic reticulum stress.

Cartilage Ablation of Sirt1 Causes Inhibition of Growth Plate Chondrogenesis by Hyperactivation of mTORC1 Signaling.

A growing body of evidence implies a pivotal role of sirtuin-1 (Sirt1) in chondrocyte function and homeostasis; however, its underlying mechanisms mediating chondrogenesis, which is an essential process for physiological skeletal growth, are still poorly understood. In the current study, we generated TamCartSirt1-/- [Sirt1 conditional knockout (cKO)] mice to explore the role of Sirt1 during postnatal endochondral ossification. Compared with control mice, cKO mice exhibited growth retardation associated with inhibited chondrocyte proliferation and hypertrophy, as well as activated apoptosis. These effects were regulated by hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) signaling, and thereby inhibition of autophagy and induction of endoplasmic reticulum stress in growth plate chondrocytes. IP injection of the mTORC1 inhibitor rapamycin to mice with Sirt1 deletion partially neutralized such inhibitory effects of Sirt1 ablation on longitudinal bone growth, indicating the causative link between SIRT1 and mTORC1 signaling in the growth plate. Mechanistically, SIRT1 interacted with tuberous sclerosis complex 2 (TSC2), a key upstream negative regulator of mTORC1 signaling, and loss of Sirt1 inhibited TSC2 expression, resulting in hyperactivated mTORC1 signaling in chondrocytes. In conclusion, our findings suggest that loss of Sirt1 may trigger mTORC1 signaling in growth plate chondrocytes and contributes to growth retardation, thus indicating that SIRT1 is an important regulator during chondrogenesis and providing new insights into the clinical potential of SIRT1 in bone development.

Adipose-specific knockdown of Sirt1 results in obesity and insulin resistance by promoting exosomes release.

Sirtuin1 (SIRT1) has recently emerged as a pivotal regulator of glucose metabolism and insulin sensitivity. However, the underlying mechanism has not been fully elucidated. In this study, we investigated the role of SIRT1 in the development of obesity and insulin resistance by generating mice with adipose-specific ablation of Sirt1 (Ad-Sirt1-/- mice). Ad-Sirt1-/- mice exhibited increased fat mass, impaired glucose tolerance, attenuated insulin sensitivity, and increased exosomes, whereas the administration of exosomes inhibitor effectively ameliorated the impaired metabolic profile in Ad-Sirt1-/- mice. Moreover, the increased exosomes were proved to be a result of defective autophagy activity in Ad-Sirt1-/- mice and restoration of SIRT1 activity efficiently improved metabolic profiles in vitro. Further study demonstrated that Sirt1 deficiency-induced exosomes modulated insulin sensitivity at least partially via the TLR4/NF-κB signaling pathway. Therefore, our findings implicated SIRT1 as a key factor in metabolic regulation, and adipose Sirt1 deficiency could exert an effect on the development of obesity and insulin resistance by promoting exosome release.

Deletion of clock gene Bmal1 impaired the chondrocyte function due to disruption of the HIF1α-VEGF signaling pathway.

Several studies have demonstrated the core circadian rhythm gene Bmal1 could regulate the clock control genes (CCGs) expression and maintain the integrity in cartilage tissue. In addition, its abnormal expression is connected with the occurrence and development of several diseases including osteoarthritis (OA). However, the relationship between Bmal1 and cartilage development still needs to be fully elucidated. Here, we bred tamoxifen-induced cartilage-specific knockout mice to learn the effects of Bmal1 on the cartilage development and its underlying mechanisms at specific time points. We observed that Bmal1 ablated mice showed growth retardation during puberty, and the length of whole growth plate and the proliferation zone were both shorter than those in the control group. Deletion of Bmal1 significantly inhibited the chondrocytes proliferation and activated cells apoptosis in the growth plate. Meanwhile, knockout of Bmal1 attenuated the expression of VEGF and HIF1α and enhanced the level of MMP13 and Runx2 in the growth plate chondrocytes. Consistent with these findings in vivo, ablation of Bmal1 could also lead to decrease chondrocytes proliferation, the expression of HIF1α and VEGF and elevate apoptosis in cultured chondrocytes. These findings suggest that Bmal1 plays a pivotal role in cartilage development by regulating the HIF1α-VEGF signaling pathway.

PlantMP: a database for moonlighting plant proteins.

Moonlighting proteins are single polypeptide chains capable of executing two or more distinct biochemical and/or biological functions. Here, we describe the development of PlantMP, which is a manually curated online-based database of plant proteins that are known to `moonlight'. The database contains searchable UniProt IDs and names, canonical and moonlighting functions, gene ontology numbers, plant species as well as links to the PubMed indexed articles. Proteins homologous to experimentally confirmed moonlighting proteins from the model plant Arabidopsis thaliana are provided as a separate list of `likely moonlighters'. Additionally, we also provide a list of predicted Arabidopsis moonlighting proteins reported in the literature. Currently, PlantMP contains 110 plant moonlighting proteins, 10 `likely moonlighters' and 27 `predicted moonlighters'. Organizing plant moonlighting proteins in one platform enables researchers to conveniently harvest plant-specific raw and processed data such as the molecular functions, biological roles and structural features essential for hypothesis formulation in basic research and for biotechnological innovations.